The prevalence of neurodegenerative disorders similar to Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) is unusually high among Chamorros in the Mariana Islands. Despite similarities between these Chamorro diseases (known as Guam ALSIPDC) and AD, PD or ALS elsewhere, the predominant findings in Guam ALS/PDC brains are abundant neurofibrillary tangles (NE;Ts) like those in classic AD. For example, the major structural elements of NFTs AD and Guam ALS/PDC are paired helical filaments (PHFs), and previous studies showed that the PHFs in AD and Guam ALSIPDC are formed from abnormally phosphorylated tau proteins (PHFtau). Although, we showed that biopsy derived normal adult human tau is phosphorylated at nearly all of the sites previously identified in AD PHFtau, albeit to a lesser extent, biopsy derived normal human tau undergoes rapid and selective dephosphorylation at sites that are abnormally retained in PHFtau. We also provided data to suggest that differences in the phosphorylation state of normal human tau versus PHFtau may be due to impaired phosphatase activity in the AD brain. Indeed, protein phosphatase 2A (PP2A) was implicated in the failure of PHFtau to undergo efficient dephosphorylation. Since PP2A dephosphorylates tau, alterations in the accessory, catalytic and regulatory subunits of PP2A could play a central role in the generation of PHFtau. Although the degeneration of neurons in Guam ALSIPDC is associated almost exclusively with the accumulation of NFTs, and the levels of tan in the cerebrospinal fluid (CSF) of AD patients are elevated relative to controls, the pathogenesis and biological significance of accumulations of PHFtau in neurofibrillary lesions in AD and Guam ALS/PDC are poorly understood. Thus, Project 4 will test the hypothesis that PHFtau-rich neurofibrillary lesions play a role in the degeneration of neurons in Guam ALS/PDC. To accomplish this, we will assess the biological significance of elevated levels of CSF tan, examine the role of PP2A in the pathogenesis of PHFtau and tangle formation, and characterize the molecular profile of tangle bearing versus normal neurons in the brains of patients with and without Guam ALS/PDC. These studies will provide important insights into the pathogenesis of PHFtau in the hallmark lesions of Guam ALS/PDC, and clarify how these lesions lead to neuron loss in Guam ALS/PDC.